Clinical and Economic Outcomes in Medicare Beneficiaries with Stage 3 or Stage 4 Chronic Kidney Disease and Anemia: The Role of Intravenous Iron Therapy

BACKGROUND: Anemia in patients with chronic kidney disease (CKD) is associated with increased morbidity and mortality, decreased quality of life, and substantial health care costs. Iron therapy is recommended, usually in combination with an erythropoiesis-stimulating agent (ESA), in many CKD patients with anemia and low iron levels to raise hemoglobin levels to a range of 10 to 12 grams per deciliter; iron deficiency is defined by a ferritin score less than 100 micrograms (mcg) per liter and transferrin saturation (TSAT) less than 20%. OBJECTIVES: To examine the use of intravenous (IV) iron and it's associated economic and clinical outcomes in Medicare beneficiaries with stage 3 or stage 4 CKD and anemia. METHODS: This was a retrospective cohort analysis using 2006 and 2007 Medicare 5% Standard Analytic Files (SAF). Use of therapy with IV iron and/or ESAs was identified among patients diagnosed with CKD and anemia. The study index quarter was the first quarter in 2006 during which the patient had primary or secondary diagnoses of both CKD and anemia. Based on the receipt of IV iron or ESA treatment in the index quarter, patients were classified into 1 of 4 treatment groups: IV iron and ESA; IV iron without ESA; ESA without IV iron; neither IV iron nor ESA. Therapy with oral iron was not measurable with this database. Clinical and economic outcomes, including the progression to advanced CKD stages, development of anemia, mortality, hospitalization, and net Medicare reimbursement (i.e., not including patient or supplemental plan contribution) for all-cause health care services, were examined for 1 year following the index quarter. Between-group differences were tested using Pearson chi-square for categorical variables and the Kruskal-Wallis nonparametric test for reimbursement. Multivariate logistic regression models were estimated to assess the associations of mortality, inpatient hospitalization, skilled nursing facility (SNF) admission, and hospice care with treatment regimen, controlling for patient demographic and clinical characteristics. RESULTS: Of the 4,310 study patients with both CKD and anemia, 2,913 (67.6%) received neither IV iron nor ESA; 984 (22.8%) received ESA without IV iron; 277 (6.4%) received IV iron and ESA; and 136 (3.2%) received IV iron without ESA in the index quarter. Logistic regression analyses showed that patients receiving neither IV iron nor ESA (reference group) were at increased risk of death compared with patients receiving both IV iron and ESA (OR = 0.62, 95% CI = 0.42-0.90). Additionally, patients receiving neither IV iron nor ESA were more likely to be hospitalized compared with patients receiving both IV iron and ESA (OR = 0.66, 95% CI = 0.50-0.87), IV iron without ESA (OR = 0.55, 95% CI = 0.38-0.79), and ESA without IV iron (OR = 0.73, 95% CI = 0.62-0.87). Further, patients not receiving IV iron or ESA were more likely to be admitted to an SNF than patients receiving both IV iron and ESA (OR = 0.44, 95% CI = 0.32-0.61), IV iron without ESA (OR = 0.57, 95% CI = 0.36-0.88), and ESA without IV iron (OR = 0.56, 95% CI = 0.47-0.67). Patients receiving neither IV iron nor ESA in the index quarter had the highest mean [SD] total Medicare reimbursement per patient in the subsequent year ($42,353 [$52,887]) compared with patients receiving IV iron without ESA ($28,654 [$32,068]), IV iron and ESA ($34,152 [$30,506]), or ESA without IV iron ($38,172 [$35,591], P = 0.001). CONCLUSIONS: Use rates of IV iron and ESA in a sample of Medicare enrollees with CKD and anemia in 2006 suggest that anemia management therapies may be underutilized; however, oral iron therapy use was not measurable with the study database, and therapies initiated after the index quarter were not measured. Patients not treated with IV iron or ESA had significantly higher rates of hospitalization and SNF admission than patients treated with either IV iron or ESA. Further, mortality was significantly higher in patients receiving neither IV iron nor ESA than in patients who received IV iron and ESA. Additionally, total all-cause health care costs were higher among patients receiving neither IV iron nor ESA treatment compared with patients treated with IV iron and/or ESA.


R E S E A R C H
• Anemia is a common occurrence in patients with chronic kidney disease (CKD), with reported prevalence rates of 9%-64% depending on CKD stage and definition of anemia and is associated with increased morbidity and mortality. In a sample of patients with incident CKD, Thorp et al. (2009) found that patients with severe anemia (hemoglobin less than 10.5 grams per deciliter) had higher odds of mortality (hazard ratio [HR] = 5.27, 95% CI = 4.37-6.35), cardiovascular hospitalizations (HR = 2.18, 95% CI = 1.76-2.70), and end-stage renal disease (HR = 5.46, 95% CI = 3.38-8.82) compared with patients without anemia. • Clinical guidelines from the National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK, 2008) recommend the use of iron supplements (oral or intravenous [IV]) in CKD patients with anemia (defined as hematocrit less than 33% in women of childbearing age or less than 37% in men and postmenopausal women) in whom therapy with an erythropoiesisstimulating agent (ESA) does not raise the hematocrit above the threshold levels because iron levels are too low. Iron deficiency is defined in the NIDDK guidelines as a ferritin score less than 100 micrograms (mcg) per liter and a transferrin saturation (TSAT) score less than 20%. • While previous research has demonstrated the effectiveness of IV iron therapy in correcting anemia in some patients with CKD, the clinical and economic outcomes associated with IV iron therapy compared with other treatments including ESA in routine clinical practice are unknown.

What is already known about this subject
ABSTRACT BACKGROUND: Anemia in patients with chronic kidney disease (CKD) is associated with increased morbidity and mortality, decreased quality of life, and substantial health care costs. Iron therapy is recommended, usually in combination with an erythropoiesis-stimulating agent (ESA), in many CKD patients with anemia and low iron levels to raise hemoglobin levels to a range of 10 to 12 grams per deciliter; iron deficiency is defined by a ferritin score less than 100 micrograms (mcg) per liter and transferrin saturation (TSAT) less than 20%.
OBJECTIVE: To examine the use of intravenous (IV) iron and its associated economic and clinical outcomes in Medicare beneficiaries with stage 3 or stage 4 CKD and anemia.

METHODS: This was a retrospective cohort analysis using 2006 and 2007
Medicare 5% Standard Analytic Files (SAF). Use of therapy with IV iron and/or ESAs was identified among patients diagnosed with CKD and anemia. The study index quarter was the first quarter in 2006 during which the patient had primary or secondary diagnoses of both CKD and anemia. Based on the receipt of IV iron or ESA treatment in the index quarter, patients were classified into 1 of 4 treatment groups: IV iron and ESA; IV iron without ESA; ESA without IV iron; neither IV iron nor ESA. Therapy with oral iron was not measurable with this database. Clinical and economic outcomes, including the progression to advanced CKD stages, development of anemia, mortality, hospitalization, and net Medicare reimbursement (i.e., not including patient or supplemental plan contribution) for all-cause health care services, were examined for 1 year following the index quarter.
Between-group differences were tested using Pearson chi-square for categorical variables and the Kruskal-Wallis nonparametric test for reimbursement. Multivariate logistic regression models were estimated to assess the associations of mortality, inpatient hospitalization, skilled nursing facility (SNF) admission, and hospice care with treatment regimen, controlling for patient demographic and clinical characteristics. is associated with substantial health care costs, 9 possibly because it serves as a marker for disease severity. 10 Anemia treatment in patients with CKD to Hb or hematocrit targets that have varied among different studies has been associated with improvements in quality of life, sexual function, muscle strength, endurance, reduced risk of hospitalization, and improved cardiovascular outcomes. [11][12][13][14][15][16] The correction of anemia in patients with congestive heart failure also has been associated with improved outcomes, including improved cardiac function, a reduction in the number of hospitalizations, and slowed progression of both heart and renal failure. 17 Anemia in patients with CKD is treated with erythropoiesisstimulating agents (ESAs), intravenous (IV) or oral iron, and less commonly, blood transfusions. Recommendations for clinical practice promulgated by the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-KDOQI, 2006) vary according to patient hemodialysis status, the underlying cause of anemia, and other factors. 18 For patients undergoing hemodialysis, ESAs are the mainstay of treatment. 18 For patients not undergoing hemodialysis, clinical practice guidelines suggest that iron agents may be used as primary treatment or as adjuvant therapy for patients treated with ESAs. 18,19 For those patients with decreased EPO production and iron deficiency, a combination of ESAs and iron may be used; iron deficiency reduces the effectiveness of ESAs to stimulate the production of red blood cells, thereby interfering with their ability to raise a patient's Hb level. 20 Clinical guidelines from the National Institute for Diabetes and Digestive and Kidney Diseases (NIDDK, 2008) recommend the use of oral or IV iron supplements in CKD patients with anemia (defined as hematocrit less than 33% in women of childbearing age or less than 37% in men and postmenopausal women) in whom therapy with an ESA does not raise the hematocrit above the threshold levels because iron levels are too low. 19 Iron deficiency is defined in the NIDDK guidelines as a ferritin score less than 100 micrograms (mcg) per liter and a transferrin saturation (TSAT) score less than 20%. 19 In their investigation of 47 nondialyzed patients with CKD and Hb less than 12 gm per dL, Gotloib et al. (2006) observed that replenishing iron stores significantly increased mean (standard deviation [SD]) Hb levels from 10.16 (1.32) gm per dL to 11.96 (1.52) gm per dL. 21 According to NKF-KDOQI (2006) guidelines, IV iron is strongly recommended over oral iron for iron deficient CKD patients who are hemodialysis-dependent. For patients who are nondialyzed (ND-CKD) or peritoneal dialysis-dependent, the guidelines do not indicate a preference for oral or IV iron. 18 The effective use of oral iron therapy may be limited in patients with CKD due to insufficient intestinal absorption and gastrointestinal complaints that may reduce patient compliance with treatment. 22 Three of the four published randomized controlled trials that examined the efficacy of treatment with IV and oral iron in anemic, ND-CKD patients indicated that IV iron was more efficacious than oral iron, 23,24,25 whereas a fourth showed no added benefit from IV iron. 26 Taken together, these studies A n estimated 26 million adults in the United States have chronic kidney disease (CKD). 1 Patients with CKD have a high burden of morbidity and mortality. In its early stages (stages 1 and 2), CKD is often asymptomatic, but affected individuals are at risk of progressing to later stages. 2 As kidney function declines (stages 3 and 4), patients may begin to experience fatigue, pruritus, constipation, anorexia, pain, sleep disturbance, dyspnea, nausea, restless legs, and depression. 3 Despite treatment, CKD may progress to end-stage renal disease (ESRD) or complete kidney failure, requiring the use of renal replacement therapy. 2 Anemia is a common occurrence in CKD patients and is associated with increased morbidity and mortality. 4 In a sample of patients with incident CKD, Thorp 4 Anemia is defined by a decrease in hematocrit or Hb. It develops as kidney function deteriorates primarily due to the decreased production of erythropoietin (EPO) and impairs the body's ability to provide an adequate oxygen supply to organs. 3,5 Impaired oxygen delivery can adversely affect organ function, particularly cardiac function. 2,6,7 Anemia has been shown to have a negative impact on quality of life and gives rise to symptoms such as lethargy, decreased cognition, and reduced mental acuity. 8

What this study adds
2005 were used to identify pre-existing comorbidities including diabetes, hypertension, bone disease, malnutrition, liver cirrhosis, and heart disease in the year prior to CKD diagnosis. The Medicare 5% SAF contain final action claim-level data, which can be linked across multiple years and settings of care, and represent all claims for 5% of Medicare beneficiaries in a given year. Medicare beneficiaries remain in the SAF until they no longer receive Medicare benefits or expire. The SAF data include separate files for hospital inpatient, hospital outpatient, physician/supplier Part B, skilled nursing facility (SNF), home health, hospice, durable medical equipment (DME) claims, and a demographic file that indicates age, gender, date of death (if applicable), and eligibility information. Each beneficiary is assigned an encrypted identifier by the Centers for Medicare & Medicaid Services (CMS) that protects the identity of the patient but allows for researchers to track a patient from one year to the next or across different practice settings. To further protect patient confidentiality, the SAF data do not provide actual dates of service; rather, quarters of service are provided in the claims data. Institutional Review Board (IRB) review or determination was not sought as no patient-identifying information was used in the analysis.
As an initial step, all claims with a primary or secondary International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis code for stage 3 (585.3) or stage 4 (585.4) CKD were selected from the 2006 SAF claims data. Claims data from 2006 were used to identify an index stage 3 or 4 diagnosis because 2006 was the first year that CKD stage could be determined from the ICD-9-CM diagnosis code. If the first identification of stage 3 CKD diagnosis occurred in the same quarter as a stage 4 CKD diagnosis, then the patient was classified as a stage 4 CKD patient. If the first identification of a stage 3 or 4 CKD diagnosis occurred in the same quarter as a stage 5 CKD or end-stage renal disease (ESRD) diagnosis, the patient was excluded from the analysis because those patients had greater disease severity than the intended patient population.
Using this method, the index quarter identified the initial quarter of CKD diagnosis in 2006. Because data for 2005 were not examined for CKD diagnosis, the first diagnosis in 2006 was not necessarily the first diagnosis of CKD for the patient (i.e., the CKD might or might not have been newly diagnosed). Four quarters of data were then extracted after the index quarter to investigate clinical outcomes, medical resource use, and mortality. Only patients with continuous eligibility in all 5 quarters or with continuous eligibility through their quarter of death were included in the analysis.

Study Sample
The sample of patients with stages 3 or 4 CKD was divided into 10 subgroups based on combinations of the following characteristics: with and without anemia, with and without IV iron therapy, with and without ESA treatment, and specific combinations of IV iron therapy and ESA treatment (Figure suggest that IV iron may modestly improve efficacy compared with oral iron for patients with ND-CKD. However, IV iron is also associated with adverse effects including hypotension, flushing, and the potential risk of hypersensitivity reactions including anaphylaxis. 27, 28,29 The product label for iron dextran injection includes a black box warning specifying that it should be used "only in patients in whom clinical and laboratory investigations have established an iron deficient state not amenable to oral iron therapy" and that prior to administration at a therapeutic dose, a test dose should be administered. 27 Iron sucrose and sodium ferric gluconate complex do not have the black box warning and do not require a test dose. 28,29 Although the treatment of anemia in patients with CKD has predominantly been focused on ESAs, the results of several recent randomized, placebo-controlled studies have raised new safety concerns with these therapies when used to achieve Hb targets higher than 10-12 gm per dL 30,31,32 leading to a reevaluation of their use. In the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) study, for example, rates on the primary end point outcome (a composite of all-cause death, stroke, or cardiovascular events) did not significantly differ for ND-CKD patients treated with placebo versus darbepoetin alfa dosed to a target Hb of 13 gm per dL, and the risk of stroke was nearly twice as high for the patients treated with darbepoetin alpha. 30 Further, there is a discrepancy between the NKF-KDOQI guidelines, which suggest ESA treatment to target Hb levels to 11-12 gm per dL (Hb range recommendations, updated 2007), 18 and the ESA product labels, which indicate that Hb levels should be targeted to 10-12 gm per dL. 33, 34 Given the more recent safety concerns associated with ESA use, we may expect the practice of targeting higher Hb levels with ESAs to decline.
Despite the importance placed on treating anemia in patients with CKD, many receive inadequate treatment, as evidenced by the low Hb levels often seen in individuals with CKD. 35,36 Among patients with ND-CKD, Voormolen et al. (2010) found that 48% had Hb of 11 gm per dL or less at the start of care, 37 and McClellan et al. (2004) found that rates of anemia defined as Hb 10 gm per dL or less and 12 gm per dL or less were 8.9% and 47.7%, respectively. 36 In a study of patients treated for CKD in nephrology clinics, Kammerer et al. (2002) found that 26.3% had Hb below 10 gm per dL, 46.7% had Hb below 11 gm per dL, and 63.9% had Hb below 12 gm per dL. 38 The purpose of this study was to examine the use of IV iron and its associated economic and clinical outcomes among Medicare beneficiaries with stage 3 or stage 4 CKD and anemia.

■■ Methods Study Design and Data Sources
In this retrospective study, clinical outcomes, mortality, and medical resource use for patients with stages 3 or 4 CKD and anemia were examined among Medicare beneficiaries in the United States in years 2006 and 2007 using the Medicare 5% Standard Analytic Files (SAF). 39 For these patients, data from quarter were not measured. Oral iron use was not assessed because prescription claims data were not available in this database.

Construction of Outcome and Treatment Variables
Outcomes were investigated in the index quarter and the subsequent 4 quarters. Clinical outcomes, including the progression to advanced CKD stages, development of anemia, and development of coronary disease, were identified using appropriate ICD-9-CM codes (Table 1) in the 4 quarters following the index quarter. Disease progression was defined as having a claim in any of the 4 follow-up quarters with a primary or secondary diagnosis of a more advanced stage of CKD compared with the index quarter (e.g., at least 1 claim for stage 4 CKD in a patient classified in the index quarter as having stage 3 CKD). Patients who progressed to ESRD were not censored and were followed in the same way as all other study patients. Specific treatments of iron sucrose, iron dextran, iron gluconate, darbepoetin alfa and epoetin alfa, blood transfusion, and dialysis were identified by appropriate CPT, HCPCS, and ICD-9-CM procedure codes (Table 2). Medical resource use was identified using inpatient, hospital outpatient, physician office, SNF, hospice, home health, DME, and emergency room claims. Total length of stay (LOS) per patient for the 4-quarter period following index quarter in the inpatient, SNF, and hospice settings was collected. Total net Medicare reimbursement (not including patient or supplemental plan contribution) was collected for each of these settings and reported in 2007 U.S. dollars (USD). Dollar amounts from years prior to 2007 were converted to 2007 USD using the medical care component of the Consumer Price Index. 40 The Medicare reimbursement amounts for each treatment were collected and converted to 2007 USD.

Statistical Analysis
Analyses were performed for patients with a diagnosis of stage 3 or stage 4 CKD and for subgroups ( Figure 1). Descriptive statistics were calculated on demographic characteristics at baseline and on clinical characteristics in the year prior to the index quarter. Clinical characteristics included number of comorbid conditions (diabetes, hypertension, bone disease, malnutrition, liver cirrhosis, and heart disease) and proportion of patients with each pre-identified comorbidity. Additional data analyzed in the 4 follow-up quarters included clinical outcomes and Medicare reimbursed amounts in total and for all 7 settings of care.
Comparisons were made among 4 key subgroups of patients with anemia, defined based on treatment in the index quarter: IV iron and ESA, IV iron without ESA, ESA without IV iron, and neither IV iron nor ESA treatment. Pearson chi-square tests were used to compare the demographic characteristics, mortality, inpatient hospitalization, admission to either SNF or hospice, and the proportion of patients progressing to advanced CKD stages. Given the large sample size and the expected normal distributions of age and LOS, Student's t-tests were used to compare those outcomes. However, Kruskal-Wallis nonparametric tests were used to compare Medicare reimbursement because distributions of cost data are typically skewed.
Multivariate logistic regression analyses on the outcomes of mortality, hospitalization, and admission to SNF or hospice, were performed while adjusting for covariates, including demographics, treatment group, and comorbidities (diabetes, hypertension, heart disease, bone disease, malnutrition, and liver cirrhosis) measured in the year prior to the index quarter. The regression analyses were performed by specifying the occurrence of each outcome event (mortality, occurrence of hospitalization, admission to SNF, and receipt of hospice care) as the dependent variable and forcing demographic characteristics (age, gender, Medicare eligibility category, and race) and treatment group (reference group of IV iron and ESA, IV iron without ESA, ESA without IV iron, and neither IV iron   CKD stages or death was calculated; however, the proportion of patients progressing to later CKD stages or dying was not significantly different among the 4 patient groups (P = 0.062).
Compared with the other treatment groups, patients receiving neither IV iron nor ESA were more likely to be hospitalized (64.0%-71.7% vs. 78.0%, respectively, P < 0.001) or admitted to SNF (17.7%-22.6% vs. 34.1%, respectively, P < 0.001; Table  4). As a result, these patients had longer mean total LOS for all settings of care ( Multivariate logistic regressions showed that patients receiving neither IV iron nor ESA (reference group) were at increased risk for the outcome of death compared with the group of patients receiving both IV iron and ESA (odds ratio [OR] = 0.62, 95% CI = 0.42-0.90; Table 5). Additionally, patients receiving neither IV iron nor ESA were more likely to be hospitalized compared with patients receiving both IV iron and ESA (OR = 0.66, 95% CI = 0.50-0.87), IV iron without ESA (OR = 0.55, 95% CI = 0.38-0.79), and ESA without IV iron (OR = 0.73, 95% CI = 0.62-0.87). Further, patients not receiving IV iron or ESA were more likely to be admitted to an SNF than patients receiving both IV iron and ESA (OR = 0.44, 95% CI = 0.32-0.61), IV iron without ESA (OR = 0.57, 95% CI = 0.36-0.88), and ESA without IV iron (OR = 0.56, 95% CI = 0.47-0.67). There was no statistical difference between the groups for the proportion of patients receiving hospice care. Among the subgroup of 1,397 patients treated with ESA and/or IV iron, odds of mortality for those receiving ESA without IV iron were 54% higher compared with patients receiving IV iron and ESA (OR = 1.535, 95% CI = 1.025-2.296; data not shown). No other outcomes had significant results among the subgroup of patients treated with ESA and/or IV iron.
Each additional year of age was associated with increased odds of death (OR = 1.07; 95% CI = 1.06-1.08), inpatient hospitalization (OR = 1.03, 95% CI = 1.02-1.04), SNF admission (OR = 1.07, 95% CI = 1.06-1.08), and hospice care (OR = 1.08; 95% CI = 1.06-1.10; data not shown). Patients who were Asian, Hispanic, or a race other than white or black were less likely to die (OR = 0.59, 95% CI = 0.38-0.92), be hospitalized (OR = 0.70, 95% CI = 0.50-0.97), be admitted to an SNF (OR = 0.47, 95% CI = 0.32-0.69), or receive hospice care (OR = 0.35, 95% CI = 0.17-0.73; data not shown). Of the 6 pre-existing comorbidities that were investigated, malnutrition and liver cirrhosis were significant predictors in all 4 outcomes. History of diabetes was predictive of death, inpatient hospitalization, and SNF admission. Conversely, history of bone disease was inversely associated with death, inpatient hospitalization, and SNF admission, with ORs all less than 1.00 for these outcomes. History of nor ESA) variables in the model. The remaining covariates were introduced into the model in a forward stepwise fashion (P value for entry = 0.10) using Wald chi-square goodness-of-fit tests.
Statistical significance was evaluated at the 0.05 level. All statistical analyses were performed using SAS version 9.1.3 (SAS Institute Inc., Cary, NC).

■■ Results
Of 37,472 patients with stage 3 or stage 4 CKD in the SAF database, 4,310 (11.5%) also had an anemia diagnosis in the index quarter (Figure 1). Of these patients, 413 (9.6%) received IV iron treatment in the index quarter, and 1,261 (29.3%) received ESA treatment in the index quarter. The majority of sample patients receiving IV iron also received ESA treatment (277 [67.1%] of 413 IV iron users, 6.4% of the sample overall), and 136 patients (3.2% of the sample) received IV iron without ESAs. Less than one-quarter of patients receiving ESA treatment also received IV iron (277 [22.0%] of 1,261 ESA users).

Comparisons Among 4 Key Treatment Subgroups
Across the 4 patient groups, age was statistically different, with the group of patients treated with IV iron and not ESAs a mean of 3.5 to 4.0 years younger than the other groups (P < 0.001; Table 3). There was no significant difference in gender among the groups (P = 0.502). Most patients (78.5%-85.3%) in each treatment group were white with slightly higher percentages of white patients in the IV iron and ESA and IV iron without ESA groups (85% in each, P = 0.011).
During the index quarter, a larger proportion of patients in the IV iron and ESA group had stage 4 CKD (49.8%) compared with the other groups (39.0% IV iron without ESA, 44.4% ESA without IV iron, 32.1% neither IV iron nor ESA, P < 0.001). Approximately 7% of all sample patients received dialysis in the year following the index quarter, and dialysis was most commonly used in the ESA without IV iron group (9.5%) followed by the group with neither IV iron nor ESA (6.1%), IV iron and ESA (< 5.0%), and IV iron without ESA (< 5.0%, P = 0.002).
Progression to advanced CKD stages was more common among patients receiving either IV iron or ESAs (progression rates of 27.2%-31.0%) compared with those not receiving either treatment (progression rate of 22.6%; Table 4). For patients treated with IV iron and/or an ESA (n = 1,397), there was no significant difference among treatment groups in the proportions advancing to later CKD disease stages (P = 0.655; not shown in table).
The mortality analysis showed that 20.5% of the subgroup receiving neither IV iron nor ESA died in the year following the index quarter, compared with mortality rates of 18.1% for ESA without IV iron, 11.0% for IV iron without ESA, and 12.6% for IV iron and ESA (P < 0.001). For the 1,397 patients receiving IV iron and/or ESA, the difference in mortality rates among the 3 treatment groups was statistically significant (P = 0.020; not shown in table). A composite measure of progression to later Within this sample of Medicare beneficiaries, stage 3 and stage 4 CKD patients with anemia who were treated with ESA and/or IV iron during the index quarter experienced more favorable outcomes in the subsequent year than those patients receiving neither ESA nor IV iron therapy. In the unadjusted bivariate results, the study cohorts who received IV iron, ESA, or both demonstrated lower mortality than those receiving neither IV iron nor ESA. After adjusting for demographics and pre-index comorbidities, those treated with both IV iron and ESA still had a significantly lower risk of death in the year hypertension was a significant predictor of hospitalization and hospice care.

■■ Discussion
In a sample of Medicare beneficiaries with stage 3 or stage 4 CKD and anemia, 29.3% received ESA therapy and 9.6% received IV iron during a study index quarter within which the patient received diagnoses of both CKD and anemia for the first time in 2006. Although anemia treatment may not be indicated for all patients, greater utilization of these treatments may be expected; however, oral iron therapy was not measurable in the  following index than did patients not treated with IV iron or ESA. Among the cohorts treated with IV iron and/or ESA, the unadjusted results showed that those receiving IV iron without ESA had the lowest mortality, followed by those receiving IV iron and ESA, and those receiving ESA without IV iron. However, the adjusted results failed to show significant differences between those receiving IV iron without ESA and the other 2 treatment groups. Patients receiving neither IV iron nor ESA were also more likely to be hospitalized and admitted to an SNF during follow-up than patients treated with ESA and/ or IV iron. Interestingly, although patients treated with either IV iron and/or ESA demonstrated lower mortality and lower rates of hospitalization, those treated with either IV iron and/ or ESA had higher rates of progression to advanced stages of CKD. Finally, study patients who received neither ESA nor IV iron therapy incurred the highest mean all-cause Medicare reimbursements of all groups examined. Among the treated cohorts, those receiving IV iron without ESA had the lowest mean Medicare reimbursements, followed by those receiving IV iron and ESA and those receiving ESA without IV iron.
Current approaches to the treatment of anemia in patients with CKD emphasize the use of ESA. In our study, almost 30%

Clinical and Economic Outcomes in Medicare Beneficiaries with Stage 3 or Stage 4
Chronic Kidney Disease and Anemia: The Role of Intravenous Iron Therapy were unable to capture all medication costs (including oral iron). Given that only 7% of patients in our study received dialysis during the 1-year period following the index diagnosis, and that treatment guidelines suggest no preferred route of iron administration in CKD patients not receiving dialysis, it is reasonable to assume that a certain proportion of patients in each study cohort may have received oral iron. Other oral medications such as those used to treat worsening hypertension are also missed due to the lack of pharmacy data in our analysis.
Fourth, the assignment of treatment group was made based on the treatment received in the index quarter only. Therefore, for example, it is possible that some patients who did not receive either IV iron or ESA in the index quarter may have received one or both of the treatments in a subsequent quarter but still were labeled as "neither IV iron nor ESA." Similarly, a patient assigned to either IV iron without ESA or ESA without IV iron may have received the alternate treatment during the 1-year follow-up.
Fifth, an inherent limitation of administrative claims analyses is the reliance on the accuracy of coding in the claims. Anemia is unlikely to be the primary diagnosis on a medical claim for a CKD patient, and as the patient may have more serious comorbidities, anemia may not be recorded as a secondary diagnosis. Thus, it is possible that an anemia diagnosis may have been missed on a claim form in the initial quarter of CKD diagnosis for some patients. As a result, some CKD patients with anemia may have been misclassified and thus not included in this analysis. The possibility that an anemia diagnosis may be required to receive reimbursement for the administration of ESA or IV iron treatment suggests that few anemia patients were missed in the sampling process. However, if anemia diagnoses were recorded to ensure of patients received ESA while approximately 10% received IV iron, and less than one-third of patients with anemia and CKD in the study sample received one of these treatments in the index quarter. ESA therapy is recommended by the NKF-KDOQI to target Hb levels between 11.0 to 12.0 gm per dL (Hb range recommendations, updated 2007), 18 which differs from the labeled indication of targeting Hb levels between 10.0 to 12.0 gm per dL. 33,34 Moreover, recent clinical trial results showing increased mortality and cardiovascular morbidity of patients treated with ESA to Hb targets above those required to avoid erythrocyte transfusions have raised serious safety concerns with these therapies, and the future use of ESA seems unlikely to target Hb levels higher than 10.0 to 12.0 gm per dL (see Unger et al. [2010] for a review). 41 Additionally, particular attention to a patient's iron level should continue to be made as ESA treatment will not be effective if the patient's iron level is too low. 19

Limitations
First, the retrospective nature of this analysis does not allow for the attribution of causality between treatments and outcomes. Retrospective database studies can, however, indicate associations worthy of further investigation using additional research designs. Second, because exact dates of service are not reported in the Medicare database, dates of service were considered in this analysis in terms of quarters. As such, it was not always possible to determine which event occurred first when 2 or more events (e.g., treatment and a hospitalization) occurred within the same quarter.
Third, because of the lack of outpatient pharmacy data in the Medicare database, the use of oral iron was not evaluated. Additionally, because pharmacy data were not available, we

Clinical and Economic Outcomes in Medicare Beneficiaries with Stage 3 or Stage 4
Chronic Kidney Disease and Anemia: The Role of Intravenous Iron Therapy reimbursement for the administration of IV iron or ESA treatment, the sample may be biased to include patients receiving IV iron or ESA treatment. Sixth, the anemia diagnosis was based on the index quarter only. Although expanding the patient sample to include patients developing anemia during the 4 quarters subsequent to CKD diagnosis might have captured those missed patients, this approach would have also flagged any persons developing anemia late in the analysis period where the chances for mortality, hospitalization, and other adverse outcomes can be reduced due to a shorter observation period. By confining the anemia diagnosis to the initial quarter of CKD diagnosis, we maintained a consistent follow-up period to identify outcomes for all patient cohorts. Additionally, we noted that exposure to treatment was associated with greater progression of kidney disease and the lack of exposure to treatment was associated with greater risk of death which might be due to some form of informative censoring.
Seventh, physicians may not have treated with IV iron or ESA if the patient's illness was advanced or if the patient had comorbidities that prevented treatment. Thus, it is possible that the patients grouped into the "neither IV iron nor ESA" group simply were in poorer health compared with the other 3 groups. Contrary to this hypothesis, patients in the "neither IV iron nor ESA" group were more likely to be at stage 3 and less likely to be at stage 4 during the index quarter, compared with patients treated with IV iron and/or ESA. Additionally, most baseline comorbidity rates were similar among treatment groups. However, it is possible that unmeasured confounding factors influenced physicians' treatment decisions. The lack of detail on the claim form makes it impossible to assess this possibility fully, and further study on this subject is warranted. Finally, because we examined a Medicare population in this analysis, our results may not be generalizable to other patient populations. However, based on data from the National Health and Nutrition Examination Survey from 1999-2004 indicating that approximately 89% of all stage 3 CKD patients and 81% of stage 4/5 CKD patients are aged 60 years or older, we are confident that we have captured a large proportion of the relevant population. 42

■■ Conclusions
In this analysis of anemic stages 3 and 4 CKD patients, 29.3% received ESA therapy and 9.6% received IV iron during a study index quarter within which the patient received diagnoses of both CKD and anemia for the first time in 2006. Patients not treated with IV iron or ESA had significantly higher rates of hospitalization and SNF admission than patients treated with IV iron and/or ESA. Further, mortality was significantly higher in patients receiving neither IV iron nor ESA than in patients who received both IV iron and ESA. Additionally, mean total all-cause Medicare reimbursements were higher among patients receiving neither IV iron nor ESA treatment compared with patients treated with IV iron and/or ESA. Although it was not possible to assess the use of oral iron in the present study, the findings suggest that IV iron may be underutilized among patients with CKD and anemia.